Uric acid, a natural breakdown product of DNA, RNA and ATP, is considered to be one of the most important antioxidants in blood plasma. Most mammals rely on uricase enzymes to maintain a uric acid plasma concentration of around 1-2 mg/dl. Humans however, must rely on their kidneys to excrete most of the uric acid that is produced because the current human gene form is incapable of producing a functional uricase enzyme.
Abnormally high uric acid levels have been associated with numerous disease states, including gout and tumor lysis syndrome.
Recombinant uricases are administered for the treatment of gout and as a prophylaxis against hyperuricemia caused by tumor lysis syndrome. The currently available uricase therapeutics, which comprise nonhuman uricase enzymes, are either ineffective or elicit undesirable immune responses (sometimes leading to anaphylactic shock or even death). See U.S. Pat. Nos. 6,783,965; 7,056,713; 7,723,089 and 7,811,800 and U.S. Patent Publication No. 2009/0169534.
The present invention overcomes these problems by reconstructing and resurrecting ancestral forms of the current human uricase enzyme. Uricases of the present invention may be used therapeutically in humans to reduce uric acid levels without eliciting an undesirable immune response.